Development of a small molecule that corrects misfolding and increases secretion of Z α 1 ‐antitrypsin

Autor: Martin Rüdiger, Chun-wa Chung, Jonathan P. Hutchinson, Christopher C. Arico-Muendel, Svetlana L. Belyanskaya, Allison Olszewski, Nerina Dodic, Duncan S. Holmes, Anthony Dossang, Andrew C. Pearce, Alistair M. Jagger, Steve Wilson, Adriana Ordóñez, David A. Lomas, Toral Jakhria, Iain Uings, Hitesh Dave, Zhengrong Zhu, Stefan J. Marciniak, Alexis Denis, Lionel Trottet, Kathrine J. Smith, Murray J. B. Brown, Imran Haq, James A. Irving, Steve Skinner, Margaret Neu, Diana Klimaszewska, Peter Eddershaw, Riccardo Ronzoni, James E. Rowedder, Andrew Brewster, John Liddle, Emilie Jigorel, Jeffrey A. Messer, Ken Lind, Rebecca Terry
Přispěvatelé: Lomas, David A [0000-0003-2339-6979], Irving, James A [0000-0003-3204-6356], Ronzoni, Riccardo [0000-0002-3981-8104], Pearce, Andrew C [0000-0002-4698-037X], Apollo - University of Cambridge Repository
Rok vydání: 2021
Předmět:
Zdroj: EMBO Molecular Medicine
EMBO Molecular Medicine, Vol 13, Iss 3, Pp n/a-n/a (2021)
ISSN: 1757-4684
1757-4676
DOI: 10.15252/emmm.202013167
Popis: Severe α1‐antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1‐antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA‐encoded chemical library to undertake a high‐throughput screen to identify small molecules that bind to, and stabilise Z α1‐antitrypsin. The lead compound blocks Z α1‐antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1‐antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that “mutation ameliorating” small molecules can block the aberrant polymerisation that underlies Z α1‐antitrypsin deficiency.
A chemistry campaign has developed a small molecule that stabilises the severe Z deficiency mutant of α1‐antitrypsin. The lead compound binds to a cryptic pocket and blocks the conformational change and pathological polymerisation that underlie α1‐antitrypsin deficiency.
Databáze: OpenAIRE
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